There is growing awareness that the heart has receptors for a wide range of cytokines and growth factors, activation of which can enhance myocyte survival and growth. While there has been interest in the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis in the regulation of cardiac development and performance, only recently is it appreciated that the hypothalamic hormone, GH releasing hormone also exerts cardiac signaling activity, and that the GHRH receptor is present on myocytes. Recently, we demonstrated that a potent growth hormone releasing hormone agonist (GHRH-A: JI-38) stimulated substantial cardiac repair following acute ischemic injury without stimulating unwanted side effects associated with the GH axis. In addition, Granata et al. demonstrated that GHRH(1-44) promotes survival of cardiomyocytes following ischemia reperfusion. The availability of potent GHRH agonists offers a major new therapeutic opportunity. The overall goal of this project is to use well-validated animal models of ischemic injury and LV dysfunction (rodent and porcine, in use in our laboratory) to test the hypothesis that activation of cardiac GHRH receptors by potent agonists can reverse remodeling and improve recovery of functional performance following myocardial infarction (MI). We propose a program of work to determine the mechanism of action and manifestations of this effect. We will in three aims test the following hypothesis: To test the hypothesis that the effects of GHRH-A are mediated by direct receptor activation of the GHRH-R within the heart;To test the hypothesis that GHRH-A directly activates endogenous cardiac stem cells;Investigate the protective effects of GHRH agonist in a pig model of MI. This proposal has major implications for developing a promising new treatment strategy for the prevention and reversal of remodeling following MI. PUBLIC HEALTH RELEVANCE: We have recently discovered that growth hormone releasing hormone exerts cardioprotective effects following acute myocardial infarction. The goal of this proposal is to advance this novel observation by performing in-depth studies of the mechanism of action of this response in the situation of chronic myocardial infarction that has led to remodeling of the ventricle. In addition, we will test the very novel idea that growth hormone releasing hormone activates cardiac stem cells. Finally, we will perform translational studies in a large animal model of myocardial infarction to gain additional insights into the mechanism of action of this new signaling pathway and to advance the potential therapeutic implications of this new discovery.